Citation: Hu Yuefu, Cui Guiling, Huang Wencai, Yang Li, Qi Qingrong. Synthesis, Structural Characterization and Stability Evaluation of Metformin Hydrosulfide[J]. Chinese Journal of Organic Chemistry, ;2019, 39(5): 1503-1508. doi: 10.6023/cjoc201811031 shu

Synthesis, Structural Characterization and Stability Evaluation of Metformin Hydrosulfide

Hu Yuefu ^a ,
Cui Guiling ^a ,
Huang Wencai ^b ,
Yang Li ^c,, ,
Qi Qingrong ^a,,

a.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center of Drug Precision Industrial Technology for Small Molecule Drugs, West China School of Pharmacy, Sichuan University, Chengdu 610041
b.
School of Chemical Engineering, Sichuan University, Chengdu 610065
c.
Cancer Center, West China Hospital, Sichuan University, Chengdu 610041

Corresponding author: Yang Li, yangli@scu.edu.cn Qi Qingrong, qiqingrong@scu.edu.cn
Received Date: 26 November 2018
Revised Date: 26 December 2018
Available Online: 8 May 2019
Fund Project: the Construction of a Comprehensive Platform for the Innovation of Cardio-cerebrovascular Drugs in Shijiazhuang Pharmaceutical Group Company Limited 2013ZX09402103-1Project supported by the Construction of a Comprehensive Platform for the Innovation of Cardio-cerebrovascular Drugs in Shijiazhuang Pharmaceutical Group Company Limited (No. 2013ZX09402103-1)

Figures(2)

Hydrogen sulfide (H₂S), the third gas signal molecule in mammals is studied more and more deeply, and great progress has been made on organic small molecule hydrogen sulfide donors. However, no hydrogen sulfide donor has been marketed as a drug yet. Metformin is a first-line drug for the treatment of diabetes. And some other biological activities such as anti-obesity, anticancer, and anti-aging have been disclosed in recent years. H₂S donor has also shown promising prospect in antitumor, cardiovascular protection, anti-inflammation, ion channel regulation and anti-oxidation activities. In view of the potential of hydrogen sulfide and metformin for treatment of diseases, a novel hydrogen sulfide donor, metformin hydrosulfide, was thus designed. Till now, there is no report of this type of hydrogen sulfide donor. In our work, metformin hydrochloride was first basified to obtain metformin, followed by reaction with hydrogen sulfide to afford metformin hydrosulfide. The structure was fully characterized by ¹H NMR, ¹³C NMR, elemental analysis and X-ray crystal. The content of hydrogen sulfide was determined by iodometry method, lead acetate test and methylene blue spectrophotometric method to be more than 96.00%. The metformin level was determined by high-pressure liquid chromatography (HPLC) to be more than 98.50%. The stability of metformin hydrosulfide was evaluated by iodometry method in solution and solid, respectively. The results indicate that metformin hydrosulfide is a promising new type of hydrogen sulfide donor which deserves further research and development.
- metformin hydrosulfide,
- hydrogen sulfide donor,
- hydrogen sulfide-based therapeutics
1. [1]
  (a) Zheng, Y.; Yu, B.; De La Cruz, L. K.; Roy Choudhury, M.; Anifowose, A.; Wang, B. H. Med. Res. Rev. 2018, 38, 57.
  (b) Guo, W.; Cheng, Z. Y.; Zhu, Y. Z. Acta Pharmacol. Sin. 2013, 34, 1284.
  (c) Wallace, J. L.; Wang, R. Nat. Rev. Drug Discovery 2015, 14, 329.
  (d) Zhou, C.; Qiu, B.; Zeng, Y.; Chen, J. P.; Yu, T. J.; Li, Y. Chin. J. Org. Chem. 2017, 37, 92(in Chinese).
  (周婵, 邱波, 曾毅, 陈金平, 于天君, 李嫕, 有机化学, 2017, 37, 92.)
2. [2]
  (a) Hellmich, M. R.; Szabo, C. In Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide, Vol. 230, Eds.: Moore, P. K.; Whiteman, M., Springer, Switzerland, 2015, p. 233.
  (b) Zhao, Y.; Kang, J. M.; Park, C. M.; Bagdon, P. E.; Peng, B.; Xian, M. Org. Lett. 2014, 16, 4536.
  (c) Gao, M.; Yu, F. B.; Chen, L. X. Prog. Chem. 2014, 6, 1065(in Chinese).
  (高敏, 于发标, 陈令新, 化学进展, 2014, 6, 1065.)
3. [3]
  (a) Sparatore, A.; Santus, G.; Giustarini, D.; Rossi, R.; Del Soldato, P. Expert Rev. Clin. Pharmacol. 2011, 4, 109.
  (b) Zhang, X. Z.; Bian, J. S. ACS Chem Neurosci. 2014, 5, 876.
  (c) Zhao, Y.; Yang, C. T.; Organ, C.; Li, Z.; Bhushan, S. S.; Otsuka, H.; Pacheco, A.; Kang, J. M.; Aguilar, H. C.; Lefer, D. J.; Xian, M. J. Med. Chem. 2015, 58, 7501.
  (d) Kang, J. M.; Li, Z.; Organ, C. L.; Park, C. M.; Yang, C. T.; Pacheco, A.; Wang, D. F.; Lefer, D. J.; Xian, M. J. Am. Chem. Soc. 2016, 138, 6336.
  (e) He, P.; Tang, L. J.; Zhong, K. L.; Hou, S. H.; Yan, X. M. Chin. J. Org. Chem. 2017, 37, 423(in Chinese).
  (何平, 汤立军, 钟克利, 侯淑华, 燕小梅, 有机化学, 2017, 37, 423.)
4. [4]
  (a) Benavides, G. A.; Squadrito, G. L.; Mills, R. W.; Patel, H. D.; Isbell, T. S.; Patel, R. P.; DarleyUsmar, V. M.; Doeller, J. E.; Kraus, D. W. Proc. Natl. Acad. Sci. 2007, 104, 17977.
  (b) Liang, D.; Wu, H.; Wong, M. W.; Huang, D. Org. Lett. 2015, 17, 4196.
5. [5]
  (a) Zhao, Y.; Biggs, T. D.; Xian, M. Chem. Commun. (Camb.) 2014, 50, 11788.
  (b) Martelli, A.; Testai, L.; Citi, V.; Marino, A.; Pugliesi, I.; Barresi, E.; Nesi, G.; Rapposelli, S.; Taliani, S.; Da Settimo, F.; Breschi, M. C.; Calderone, V. ACS Med. Chem. Lett. 2013, 4, 904.
6. [6]
  (a) Martelli, A.; Testai, L.; Citi, V.; Marino, A.; Bellagambi, F. G.; Ghimenti, S.; Breschi, M. C.; Calderone, V. Vasc. Pharmacol. 2014, 60, 32.
  (b) Citi, V.; Martelli, A.; Testai, L.; Marino, A.; Breschi, M. C.; Calderone, V. Planta Med. 2014, 80, 610.
7. [7]
  Zhao, Y.; Wang, H.; Xian, M. J. Am. Chem. Soc. 2011, 133, 15. doi: 10.1021/ja1085723
8. [8]
  Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210. doi: 10.1021/cr040650b
9. [9]
  (a) Qandil, A. M. Int. J. Mol. Sci. 2012, 13, 17244.
  (b) Li, L.; Rossoni, G.; Sparatore, A.; Lee, L. C.; Del Soldato, P.; Moore, P. K. Free Radicals Biol. Med. 2007, 42, 706.
10. [10]
  (a) Wallace, J. L.; Caliendo, G.; Santagada, V.; Cirino, G.; Fiorucci, S. Gastroenterology 2007, 132, 261.
  (b) Chattopadhyay, M.; Kodela, R.; Nath, N.; Dastagirzada, Y. M.; Velazquez-Martinez, C. A.; Boring, D.; Kashfi, K. Biochem. Pharmacol. 2012, 83, 715.
11. [11]
  Lee, Z. W.; Zhou, J.; Chen, C. S.; Zhao, Y.; Tan, C. H.; Li, L.; Moore, P. K.; Deng, L. W. PLoS One 2011, 6, e21077. doi: 10.1371/journal.pone.0021077
12. [12]
  Devarie-Baez, N. O.; Bagdon, P. E.; Peng, B.; Zhao, Y.; Park, C.-M.; Xian, M. Org. Lett. 2013, 15, 2786. doi: 10.1021/ol401118k
13. [13]
  Fukushima, N.; Ieda, N.; Sasakura, K.; Nagano, T.; Hanaoka, K.; Suzuki, T.; Miyata, N.; Nakagawa, H. Chem. Commun. (Camb.) 2014, 50, 587. doi: 10.1039/C3CC47421F
14. [14]
  Fukushima, N.; Ieda, N.; Kawaguchi, M.; Sasakura, K.; Nagano, T.; Hanaoka, K.; Miyata, N.; Nakagawa, H. Bioorg. Med. Chem. Lett. 2015, 25, 175. doi: 10.1016/j.bmcl.2014.11.084
15. [15]
  Zhou, Z.; von Wantoch Rekowski, M.; Coletta, C.; Szabo, C.; Bucci, M.; Cirino, G.; Topouzis, S.; Papapetropoulos, A.; Giannis, A. Bioorg. Med. Chem. 2012, 20, 2675. doi: 10.1016/j.bmc.2012.02.028
16. [16]
  Zheng, Y.; Yu, B.; Ji, K.; Pan, Z.; Chittavong, V.; Wang, B. Angew. Chem., Int. Ed. 2016, 55, 4514. doi: 10.1002/anie.201511244
17. [17]
  Steiger, A. K.; Pardue, S.; Kevil, C. G.; Pluth, M. D. J. Am. Chem. Soc. 2016, 138, 7256. doi: 10.1021/jacs.6b03780
18. [18]
  Zheng, H.; Weng, L. L. CN 201710475428, 2017.
19. [19]
  Achterhof, M.; Conaway, R. F.; Boord, C. E. J. Am. Chem. Soc. 1931, 53, 2682. doi: 10.1021/ja01358a033
20. [20]
  Romero, R.; Erez, O.; Huttemann, M.; Maymon, E.; Panaitescu, B.; Conde-Agudelo, A.; Pacora, P.; Yoon, B. H.; Grossman, L. I. Am. J. Obstet. Gynecol. 2017, 217, 282. doi: 10.1016/j.ajog.2017.06.003
21. [21]
  Ye, Y.; Li, X. J.; Zeng, Z. Z. Chin. J. Appl. Chem. 2005, 22, 1060(in Chinese). doi: 10.3969/j.issn.1000-0518.2005.10.004
22. [22]
  (a) Moghimi, A.; Khavassi, H.; Dashtestani, F.; Kordestani, D.; Jafari, A. E.; Maddah, B.; Moosavi, S. J. Mol. Struct. 2011, 996, 38.
  (b) Veisi, H.; Masti, R.; Kordestani, D.; Safaei, M.; Sahin, O. J. Mol. Catal. A: Chem. 2014, 385, 61.
  (c) Alizadeh, A.; Khodaei, M. M.; Abdi, G.; Kordestani, D. Bull. Korean Chem. Soc. 2012, 33, 3640.
23. [23]
  Zhang, Z. L.; Bai, B.; Song, H. Chem. Eng. 2012, 26, 34(in Chinese).
24. [24]
  Guan, X. C.; Peng, H. Y. J. Anyang Inst. Technol. 2012, 11, 25(in Chinese).
25. [25]
  Koh, M.; Lee, J.-C.; Min, C.; Moon, A. Bioorg. Med. Chem. 2013, 21, 2305. doi: 10.1016/j.bmc.2013.02.015
26. [26]
  Zou, J. Y.; Feng, J. T. Sulphuric Acid Ind. 2013, 38(in Chinese).
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